Bactericidal activities of peptide antibiotics against multidrug-resistant Enterococcus faecium

Abstract

Multidrug-resistant Enterococcus faecium has emerged as a serious pathogen for which no effective therapy has been established. In this report, we describe the activities of two peptide antibiotics, ramoplanin and daptomycin, against 15 isolates of E. faecium resistant to vancomycin, ampicillin, and aminoglycosides using time-kill experiments. Both antibiotics were rapidly bactericidal when tested in broth; however, the addition of 50% serum resulted in significant regrowth. The combination of ampicillin with either ramoplanin or daptomycin largely prevented this regrowth. These peptide antibiotics showed good activity against these pathogens. While the development of daptomycin has been halted, ramoplanin may hold promise for the therapy of multidrug-resistant E. faecium, especially when combined with ampicillin.

Vancomycin-Resistant Enterococci

“…The inoculum effect was small, the agent was effectively bactericidal alone (unlike teicoplanin and vancomycin) (25,261), and there was no crossresistance with vancomycin and teicoplanin. Addition of serum to the medium impaired the in vitro activity (25,157,170,240). Variable but quite encouraging results were obtained in animal models.…”

“…In all investigations, all strains of all species, including vancomycin-resistant E. faecalis and E. faecium, were inhibited by 8 g/ml and the MIC 90 s (in all but one study) ranged from Յ0.25 to 1.6 g/ml (18,54,132,170,234). Ramoplanin is also bactericidal for enterococci, with the MBCs being only fourfold higher than the MICs (132).…”

“…Daptomycin (LY146032), an acidic lipopeptide, gave promising results in vitro. Its MICs were low in most investigations (26,48,170,234), with strains of all species of Enterococcus being inhibited by 8 g/ml and MICs at which 90% of isolates were inhibited (MIC 90 s) being recorded up to 4 g/ml; glycopeptide-resistant E. faecium strains were included (25,166). The inoculum effect was small, the agent was effectively bactericidal alone (unlike teicoplanin and vancomycin) (25,261), and there was no crossresistance with vancomycin and teicoplanin.…”

Molecular Characterization of Vancomycin-Resistant Enterococci Repopulating the Gastrointestinal Tract following Treatment with a Novel Glycolipodepsipeptide, Ramoplanin

“…No agent has been demonstrated to have efficacy for this purpose, despite the study of several candidates (novobiocin, doxycycline, bacitracin) (14,15,18,28). Ramoplanin, a glycolipodepsipeptide antimicrobial that is not systemically absorbed, has been demonstrated to have activity against VRE and has been studied as a locally active agent for the suppression of colonization (11,13,21).…”

“…No agent has been demonstrated to have efficacy for this purpose, despite the study of several candidates (novobiocin, doxycycline, bacitracin) (14,15,18,28). Ramoplanin, a glycolipodepsipeptide antimicrobial that is not systemically absorbed, has been demonstrated to have activity against VRE and has been studied as a locally active agent for the suppression of colonization (11,13,21).In a multicenter, randomized, double-blind, placebo-controlled phase II trial, ramoplanin was shown to be safe and effective at suppressing VRE to undetectable levels (at day 7) in 80 to 90% of treated patients (29). Patients colonized with VRE but without evidence of active infection were randomized to receive placebo or ramoplanin at 100 or 400 mg orally twice a day for 7 days.…”